A novel compound for colorectal cancer prevention

一种预防结直肠癌的新型化合物

基本信息

批准号：
8890808
负责人：
ARUN K SHARMA
金额：
$ 7.44万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-11 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8890808
关键词：
A/J Mouse Aberrant crypt foci Adverse effects Affect Animal Model Apoptosis Aspirin Bioavailable Biological Assay Body Weight Cause of Death Cell Proliferation Chemoprevention Chemopreventive Agent Cleaved cell Clinical Clinical Trials Colon Colon Carcinoma Colorectal Colorectal Cancer Data Development Dinoprostone Dose Dose-Rate Effectiveness Evaluation Excretory function Exhibits Future Goals Health Human Hybrids Hydrogen Cyanide Inbred F344 Rats Incidence Individual Inflammatory Intake Investigation Lead Link Literature Liver Microsomes Lung Neoplasms MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolism Minor Modeling Modification NF-kappa B National Cancer Institute Non-Steroidal Anti-Inflammatory Agents PI3K/AKT PTGS2 gene Pharmaceutical Preparations Plasma Prevention Preventive Prodrugs Property Rattus Rectum Relative (related person)Research Side Signal Pathway Signal Transduction Structure Testing Therapeutic Uses Time Tissues Toxic effect United States Validation absorption base cancer type carbene carcinogenesis colon cancer cell line colon carcinogenesis colorectal cancer prevention cyclooxygenase 1 design efficacy testing in vivo indexing innovation mortality mouse model novel pre-clinical preclinical study prevent selenocyanate selenol

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Despite the identification of several preventive agents and strategies, optimal prevention of CRC has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects. Novel compounds which are rational modifications of well-established chemopreventive agents and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. Recently, we developed highly innovative orally bioavailable hybrid molecule, p-XS- Asp, designed by conjugating two well-known chemopreventive agents i.e. 1,4-phenylene-bis(methylene)- selenocyanate (p-XSC) and nonsteroidal anti-inflammatory drug aspirin, as potential agents for CRC prevention. Both p-XSC and aspirin have shown promise as CRC chemopreventives. The advantage of the hybrid agent is two-fold: (i) the combined p-XSC-Asp would generate the active p-XSeH putative metabolite similar to p-XSC but without the toxicity related to hydrogen cyanide (HCN), that is released as a side product on p-XSC metabolism but would not form in p-XS-Asp metabolism, and (ii) the novel agent would function through releasing aspirin, thus enhancing the overall chemopreventive efficacy of the hybrid molecule. The overall goal of this project is to validate the potential of p-XS-Asp as colon cancer chemopreventive agent. We hypothesize that p-XS-Asp would cleave in vivo to release the active p-XSeH, not releasing undesired HCN but aspirin, thus making it less toxic and more potent than p-XSC or aspirin alone. The specific aims are to: 1. Determine the chemopreventive efficacy of p-XS-Asp in the F344 rat model of colorectal carcinogenesis; and 2. Evaluate the mechanism of action(s) associated with chemopreventive effects of p-XS-Asp in AOM-induced carcinogenesis. We will use the experimental approach of evaluating effectiveness of p-XS-Asp for inhibiting development of aberrant crypt foci (ACF) in F344 rats injected s.c. with AOM, once weekly for 2 weeks, at a dose rate of 15 mg/kg body weight per week. Furthermore, to begin establishing the mechanism, we will carry out metabolism of p-XS-Asp using rat liver microsomes, and evaluate its effect, relative to p-XSC and aspirin, on markers of apoptosis and cell proliferation, signaling pathways such as PI3K/AKT and MAPK, NF-kB and expression of COX-1 and COX-2 in colorectal tissues, and determine the plasma PGE2 levels of rats from different treatment groups. These studies will begin establishing the potential of p-XS-Asp as a colorectal cancer preventive agent. Long term, validation of p-XS-Asp as an effective and safe agent would reduce the chances of developing colorectal cancer thereby directly decreasing the mortality incidence.

描述（由申请人提供）：结直肠癌（CRC）是美国第二大癌症死亡原因。尽管已经确定了几种预防药物和策略，但尚未实现 CRC 的最佳预防。因此，需要更有效的药物来安全地实现预防而不产生严重的副作用。新型化合物是对成熟化学预防剂的合理改进，遵循类似的作用机制，但具有增强的效力、降低的毒性和较低的剂量需求，可能在临床上更有意义。最近，我们开发了高度创新的口服生物可利用的混合分子，p-XS-Asp，通过结合两种著名的化学预防剂，即1,4-亚苯基-双（亚甲基）-硒氰酸酯（p-XSC）和非甾体抗炎药而设计阿司匹林作为预防结直肠癌的潜在药物。 p-XSC 和阿司匹林都显示出作为 CRC 化学预防剂的前景。该混合剂的优点有两个：(i) 组合的 p-XSC-Asp 将产生与 p-XSC 类似的活性 p-XSeH 推定代谢物，但没有与释放的氰化氢 (HCN) 相关的毒性作为 p-XSC 代谢的副产物，但不会在 p-XS-Asp 代谢中形成，并且 (ii) 该新型药物将通过释放阿司匹林发挥作用，从而增强混合分子的整体化学预防功效。该项目的总体目标是验证 p-XS-Asp 作为结肠癌化学预防剂的潜力。我们假设 p-XS-Asp 会在体内裂解并释放活性 p-XSeH，而不是释放不需要的 HCN，而是释放阿司匹林，从而使其比单独的 p-XSC 或阿司匹林毒性更小且更有效。具体目的是： 1. 确定p-XS-Asp在F344大鼠结直肠癌模型中的化学预防功效； 2. 评估与 p-XS-Asp 在 AOM 诱导的癌发生中的化学预防作用相关的作用机制。我们将使用实验方法评估 p-XS-Asp 抑制皮下注射的 F344 大鼠异常隐窝病灶 (ACF) 发育的有效性。使用 AOM，每周一次，持续 2 周，剂量率为每周 15 mg/kg 体重。此外，为了开始建立机制，我们将使用大鼠肝微粒体进行p-XS-Asp的代谢，并评估其相对于p-XSC和阿司匹林对细胞凋亡和细胞增殖标志物、信号通路（例如PI3K）的影响结直肠组织中/AKT与MAPK、NF-kB以及COX-1、COX-2的表达量,并测定不同治疗组大鼠血浆PGE2水平。这些研究将开始确定 p-XS-Asp 作为结直肠癌预防剂的潜力。从长远来看，验证 p-XS-Asp 作为一种有效且安全的药物将减少患结直肠癌的机会，从而直接降低死亡率。